Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator

Autores
Zecchinati, Felipe; Ricardi, Laura Lis; Blancato, Victor Sebastian; Pereyra, Emmanuel Isidoro; Arana, Maite Rocío; Ghanem, Carolina Inés; Perdomo, Virginia; Villanueva, Silvina Stella Maris
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Background: The intestinal microbiota (IM) modulates host physiology, and its alteration (dysbiosis) is associated with numerous diseases, including obesity. This condition influences the pharmacokinetics of drugs prescribed for related comorbidities, although the underlying mechanisms remain poorly understood. Mrp2, an essential ABC transporter of the intestinal biochemical barrier, regulates the absorption of dietary toxins and orally administered drugs, modulating their bioavailability. However, its regulation in the obesity context is poorly characterized, and the role of IM alteration in this process remains unknown. Objective: To evaluate the role of the IM as a key factor, along with downstream candidate mediators, in the regulation of Mrp2 under obesity conditions. Methods: Male C57BL/6 mice were fed either a control diet or High-Fat Diet (HFD) for 8 weeks, followed by 2 weeks with or without 5% inulin, a well-known prebiotic, supplementation. Metabolic and biochemical parameters were evaluated. Intestinal barrier integrity, inflammatory cytokines, oxidative stress (OS) markers, and plasma endotoxin levels were assessed. Mrp2 expression was analyzed at mRNA and protein levels, and transporter activity was determined using the everted intestinal sac model. Fecal microbiota composition was characterized by 16S rRNA sequencing. Results: HFD feeding induced obesity, insulin resistance, hyperglycemia, dyslipidemia, intestinal dysbiosis, elevated endotoxemia, barrier dysfunction, inflammation, and OS. These alterations were associated with a marked downregulation of Mrp2 expression and activity. Inulin supplementation restored IM composition, improved metabolic and intestinal parameters, and reduced inflammation and OS. These positive changes correlated with normalization of Mrp2. Conclusions: Our findings provide the first evidence that intestinal dysbiosis, inflammation, and OS act as a central regulatory axis of intestinal Mrp2 in obesity, with the IM functioning as a key modulator.
Fil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Ricardi, Laura Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Blancato, Victor Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Pereyra, Emmanuel Isidoro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Ghanem, Carolina Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Perdomo, Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Materia
INTESTINE
OBESITY
MICROBIOTA
DYSBIOSIS
MRP2
INULIN
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/280256
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/280256
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal ModulatorZecchinati, FelipeRicardi, Laura LisBlancato, Victor SebastianPereyra, Emmanuel IsidoroArana, Maite RocíoGhanem, Carolina InésPerdomo, VirginiaVillanueva, Silvina Stella MarisINTESTINEOBESITYMICROBIOTADYSBIOSISMRP2INULINhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Background: The intestinal microbiota (IM) modulates host physiology, and its alteration (dysbiosis) is associated with numerous diseases, including obesity. This condition influences the pharmacokinetics of drugs prescribed for related comorbidities, although the underlying mechanisms remain poorly understood. Mrp2, an essential ABC transporter of the intestinal biochemical barrier, regulates the absorption of dietary toxins and orally administered drugs, modulating their bioavailability. However, its regulation in the obesity context is poorly characterized, and the role of IM alteration in this process remains unknown. Objective: To evaluate the role of the IM as a key factor, along with downstream candidate mediators, in the regulation of Mrp2 under obesity conditions. Methods: Male C57BL/6 mice were fed either a control diet or High-Fat Diet (HFD) for 8 weeks, followed by 2 weeks with or without 5% inulin, a well-known prebiotic, supplementation. Metabolic and biochemical parameters were evaluated. Intestinal barrier integrity, inflammatory cytokines, oxidative stress (OS) markers, and plasma endotoxin levels were assessed. Mrp2 expression was analyzed at mRNA and protein levels, and transporter activity was determined using the everted intestinal sac model. Fecal microbiota composition was characterized by 16S rRNA sequencing. Results: HFD feeding induced obesity, insulin resistance, hyperglycemia, dyslipidemia, intestinal dysbiosis, elevated endotoxemia, barrier dysfunction, inflammation, and OS. These alterations were associated with a marked downregulation of Mrp2 expression and activity. Inulin supplementation restored IM composition, improved metabolic and intestinal parameters, and reduced inflammation and OS. These positive changes correlated with normalization of Mrp2. Conclusions: Our findings provide the first evidence that intestinal dysbiosis, inflammation, and OS act as a central regulatory axis of intestinal Mrp2 in obesity, with the IM functioning as a key modulator.Fil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Ricardi, Laura Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Blancato, Victor Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Pereyra, Emmanuel Isidoro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaFil: Ghanem, Carolina Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; ArgentinaFil: Perdomo, Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; ArgentinaFil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; ArgentinaMDPI2025-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/280256Zecchinati, Felipe; Ricardi, Laura Lis; Blancato, Victor Sebastian; Pereyra, Emmanuel Isidoro; Arana, Maite Rocío; et al.; Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator; MDPI; Pharmaceutics; 17; 12; 12-2025; 1-251999-4923CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.mdpi.com/1999-4923/17/12/1575info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics17121575info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-02-06T13:41:51Zoai:ri.conicet.gov.ar:11336/280256instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982026-02-06 13:41:52.294CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
title Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
spellingShingle Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
Zecchinati, Felipe
INTESTINE
OBESITY
MICROBIOTA
DYSBIOSIS
MRP2
INULIN
title_short Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
title_full Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
title_fullStr Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
title_full_unstemmed Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
title_sort Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator
dc.creator.none.fl_str_mv Zecchinati, Felipe
Ricardi, Laura Lis
Blancato, Victor Sebastian
Pereyra, Emmanuel Isidoro
Arana, Maite Rocío
Ghanem, Carolina Inés
Perdomo, Virginia
Villanueva, Silvina Stella Maris
author Zecchinati, Felipe
author_facet Zecchinati, Felipe
Ricardi, Laura Lis
Blancato, Victor Sebastian
Pereyra, Emmanuel Isidoro
Arana, Maite Rocío
Ghanem, Carolina Inés
Perdomo, Virginia
Villanueva, Silvina Stella Maris
author_role author
author2 Ricardi, Laura Lis
Blancato, Victor Sebastian
Pereyra, Emmanuel Isidoro
Arana, Maite Rocío
Ghanem, Carolina Inés
Perdomo, Virginia
Villanueva, Silvina Stella Maris
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv INTESTINE
OBESITY
MICROBIOTA
DYSBIOSIS
MRP2
INULIN
topic INTESTINE
OBESITY
MICROBIOTA
DYSBIOSIS
MRP2
INULIN
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Background: The intestinal microbiota (IM) modulates host physiology, and its alteration (dysbiosis) is associated with numerous diseases, including obesity. This condition influences the pharmacokinetics of drugs prescribed for related comorbidities, although the underlying mechanisms remain poorly understood. Mrp2, an essential ABC transporter of the intestinal biochemical barrier, regulates the absorption of dietary toxins and orally administered drugs, modulating their bioavailability. However, its regulation in the obesity context is poorly characterized, and the role of IM alteration in this process remains unknown. Objective: To evaluate the role of the IM as a key factor, along with downstream candidate mediators, in the regulation of Mrp2 under obesity conditions. Methods: Male C57BL/6 mice were fed either a control diet or High-Fat Diet (HFD) for 8 weeks, followed by 2 weeks with or without 5% inulin, a well-known prebiotic, supplementation. Metabolic and biochemical parameters were evaluated. Intestinal barrier integrity, inflammatory cytokines, oxidative stress (OS) markers, and plasma endotoxin levels were assessed. Mrp2 expression was analyzed at mRNA and protein levels, and transporter activity was determined using the everted intestinal sac model. Fecal microbiota composition was characterized by 16S rRNA sequencing. Results: HFD feeding induced obesity, insulin resistance, hyperglycemia, dyslipidemia, intestinal dysbiosis, elevated endotoxemia, barrier dysfunction, inflammation, and OS. These alterations were associated with a marked downregulation of Mrp2 expression and activity. Inulin supplementation restored IM composition, improved metabolic and intestinal parameters, and reduced inflammation and OS. These positive changes correlated with normalization of Mrp2. Conclusions: Our findings provide the first evidence that intestinal dysbiosis, inflammation, and OS act as a central regulatory axis of intestinal Mrp2 in obesity, with the IM functioning as a key modulator.
Fil: Zecchinati, Felipe. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Ricardi, Laura Lis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Blancato, Victor Sebastian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; Argentina
Fil: Pereyra, Emmanuel Isidoro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Arana, Maite Rocío. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
Fil: Ghanem, Carolina Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Farmacológicas. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Investigaciones Farmacológicas; Argentina
Fil: Perdomo, Virginia. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Departamento de Microbiología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentina
Fil: Villanueva, Silvina Stella Maris. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Fisiología Experimental. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Fisiología Experimental; Argentina
description Background: The intestinal microbiota (IM) modulates host physiology, and its alteration (dysbiosis) is associated with numerous diseases, including obesity. This condition influences the pharmacokinetics of drugs prescribed for related comorbidities, although the underlying mechanisms remain poorly understood. Mrp2, an essential ABC transporter of the intestinal biochemical barrier, regulates the absorption of dietary toxins and orally administered drugs, modulating their bioavailability. However, its regulation in the obesity context is poorly characterized, and the role of IM alteration in this process remains unknown. Objective: To evaluate the role of the IM as a key factor, along with downstream candidate mediators, in the regulation of Mrp2 under obesity conditions. Methods: Male C57BL/6 mice were fed either a control diet or High-Fat Diet (HFD) for 8 weeks, followed by 2 weeks with or without 5% inulin, a well-known prebiotic, supplementation. Metabolic and biochemical parameters were evaluated. Intestinal barrier integrity, inflammatory cytokines, oxidative stress (OS) markers, and plasma endotoxin levels were assessed. Mrp2 expression was analyzed at mRNA and protein levels, and transporter activity was determined using the everted intestinal sac model. Fecal microbiota composition was characterized by 16S rRNA sequencing. Results: HFD feeding induced obesity, insulin resistance, hyperglycemia, dyslipidemia, intestinal dysbiosis, elevated endotoxemia, barrier dysfunction, inflammation, and OS. These alterations were associated with a marked downregulation of Mrp2 expression and activity. Inulin supplementation restored IM composition, improved metabolic and intestinal parameters, and reduced inflammation and OS. These positive changes correlated with normalization of Mrp2. Conclusions: Our findings provide the first evidence that intestinal dysbiosis, inflammation, and OS act as a central regulatory axis of intestinal Mrp2 in obesity, with the IM functioning as a key modulator.
publishDate 2025
dc.date.none.fl_str_mv 2025-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/280256
Zecchinati, Felipe; Ricardi, Laura Lis; Blancato, Victor Sebastian; Pereyra, Emmanuel Isidoro; Arana, Maite Rocío; et al.; Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator; MDPI; Pharmaceutics; 17; 12; 12-2025; 1-25
1999-4923
CONICET Digital
CONICET
url http://hdl.handle.net/11336/280256
identifier_str_mv Zecchinati, Felipe; Ricardi, Laura Lis; Blancato, Victor Sebastian; Pereyra, Emmanuel Isidoro; Arana, Maite Rocío; et al.; Inulin Reverses Intestinal Mrp2 Downregulation in a Diet-Induced Obesity Mouse Model: Role of Intestinal Microbiota as a Pivotal Modulator; MDPI; Pharmaceutics; 17; 12; 12-2025; 1-25
1999-4923
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.3390/pharmaceutics17121575
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
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reponame_str CONICET Digital (CONICET)
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instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.595271

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